Double redox system for disinfecting contact lenses

ABSTRACT

An improved method for rapid disinfection of contact lenses in a convenient and reliable manner is disclosed in which a series of oxidation-reduction reactions are employed. Specifically, dicheoroisocyanurate and potassium iodide react to form iodine species for disinfecting the contact lens. An amount of ascorbate is then added to neutralize the iodine species.

This is a divisional of U.S. patent application Ser. No. 07/928,643filed on Aug. 13, 1992 now abandoned, which is a continuation of U.S.patent application Ser. No. 07/526,759 filed May 22, 1990.

BACKGROUND OF THE INVENTION

The present invention relates to an improved system for disinfectinghuman worn contact lenses. More particularly, this invention relates toa composition and method for disinfecting contact lenses wherein asequence of oxidation-reduction reactions are employed to provide verypotent and rapid disinfection capability.

Numerous systems for disinfecting contact lenses have been described inthe prior art, including systems based on oxidation and reductionprinciples and systems based on the use of chlorine-containing compoundsor iodine to disinfect. Reference is made to the following publicationsfor further background regarding such systems:

European Patent Application 0 196 151 A2 (Hopkinson et al.);

U.S. Pat. No. 3,873,696 (Randeri et al.);

Canadian Patent No. 879,654 (Firth);

British Patent Specification 1 604 020 (Clough et al.);

U.S. Pat. No. 4,312,833 (Clough et al.); and

Conn et al., "Iodine Disinfection of Hydrophilic Contact Lenses," Annalsof Ophthalmology, pages 361-364 (March 1981).

Many of these prior systems have had significant drawbacks such asinadequate disinfection, inconvenience, and discoloration of contactlenses. There has, therefore, been a continuing need for a disinfectionsystem which is capable of achieving very rapid disinfection of contactlenses in a convenient and reliable manner. The present invention isdirected to the provision of an improved system which satisfies thisneed.

SUMMARY OF THE INVENTION

The contact lens disinfection system of the present invention comprisestwo basic components: a first component which achieves disinfection ofcontact lenses and a second component which neutralizes theantimicrobial agents generated by the first component. For purposes ofthe present specification, the first component is referred to as the"disinfection component" and the second component is referred to as the"neutralization component."

The disinfection component comprises an unique combination of two typesof antimicrobial agents, namely: an oxidizing agent, such as a peroxideor a hypohalite (such as sodium hypochlorite), and a reducing agent,such as an alkali metal salt of a halogen compound. The use of suchoxidizing agents to disinfect contact lenses is well known, as is theuse of halogen-containing compounds. However, the combined use of theseagents is believed to be quite unique. The combination provides a systemwherein the oxidizing agent is reduced, resulting in the generation of aproduct which is also a potent antimicrobial agent. The followingequation illustrates this principle:

    H.sub.2 O.sub.2 +3KI→2H.sub.2 O+I.sub.3.sup.-

In this example, the hydrogen peroxide acts as an oxidizing agent havingvery potent antimicrobial activity, while the potassium iodide acts toreduce the hydrogen peroxide to water and iodine. As this reaction takesplace, the initial disinfection achieved with the hydrogen peroxide israpidly supplemented by the disinfection achieved with the iodinespecies produced by the reaction. Thus, the disinfection component ofthe present invention entails the use of two very potent disinfectingagents. This allows contact lenses to be disinfected extremely rapidlyand effectively.

The neutralization component of the present invention is a reducingagent which acts to neutralize the product of the reaction between theoxidizing and reducing agents of the disinfection component, as furtherillustrated by the following equation:

    I.sub.3.sup.- +Ascorbate→3I.sup.-

The neutralization component may comprise any organic or inorganiccompound capable of reducing residual halogen resulting from thereaction of the oxidizing and reducing agents of the disinfectioncomponent.

The above-described contact lens disinfection system has numerousadvantages over prior systems. For example, the disinfection componenthas very potent antimicrobial activity and, as a result, the system iscapable of disinfecting contact lenses in less than ten minutes, whichis much more rapid than most prior disinfection methods. The system isalso much more convenient to use than prior disinfection methods becauseit simply requires the addition of one or two tablets to a solutioncontaining contaminated lenses. Further, in a preferred embodiment, thesystem is self-preserved, due to the antimicrobial activity of theneutralization component. This feature ensures that the disinfectedcontact lenses will not become recontaminated during storage subsequentto being disinfected with the disinfection component.

DETAILED DESCRIPTION OF THE INVENTION

The oxidizing agents which may be utilized in the present inventioninclude: peracids, peroxides, N-haloorganic compounds and their alkalimetal salts, chlorites, chlorine dioxide, and hypohalites. Suitableperoxides include: hydrogen peroxide, peroxyacids, peroxyesters,alkylperoxides, acylperoxides, succinic acid peroxide, organichydroperoxidates (e.g., urea peroxide or mannitol peroxide), andinorganic hydroperoxidates (e.g., alkali metal salts of perborates,percarbonates, persulfates and perphosphates). The preferred oxidizingagents are: hydrogen peroxide, the inorganic hydroperoxidates citedabove, particularly sodium percarbonate and sodium perborate, andhypochlorite-generating compounds, particularly N-chloroorganiccompounds such as dichloroisocyanurate.

The reducing agents which may be utilized in conjunction with theabove-described oxidizing agents to form the disinfection component ofthe present invention include the interhalogen compounds, which arethose halogen compounds where two different halogen atoms are combined,such as iodine monochloride. The reducing agents also include organichalides such as N-iodo succinimide and alkali metal salts of halogencompounds such as potassium iodide or potassium bromide which arecapable of: (1) reducing oxidizing agents such as hypochlorites andperoxides and (2) producing halogen species having antimicrobialactivity. The preferred reducing agent is potassium iodide.

The above-described oxidizing and reducing agents are utilized inamounts effective to eliminate substantially or to reduce significantlythe number of viable microorganisms present on contact lenses subsequentto treatment of the lenses with aqueous solutions containing acombination of these agents, in accordance with the establishedrequirements of the United States Food and Drug Administration andanalogous governmental authorities in other countries. For purposes ofthe present specification, that amount is referred to as an"antimicrobial effective amount." As will be appreciated by thoseskilled in the art, the amount of each agent utilized may vary dependingon factors such as the particular combination of agents selected, thetype of lens care regimen in which the present system is utilized (e.g.,whether a daily cleaner is used and the effectiveness of such acleaner), and the type of lens being treated (e.g., "hard" versus"soft"). In general, the disinfection component of the present inventionwill comprise one or more oxidizing agents in an amount sufficient toprovide a concentration of about 0.00001 percent by weight/volume (w/v%) to about 1.0 w/v % and one or more reducing agents in an amountsufficient to provide a concentration of about 0.001 w/v % to about 1.0w/v %. The minimum amount of reducing agent required will primarily bedetermined by the amount of oxidizing agent utilized.

The neutralization component of the present invention may be anycompound capable of reducing the halogen species produced by thedisinfection component, including: ascorbic acid and its salts andisomers, alkyl-substituted and unsubstituted sulphur-containing aminoacids, sulfites, bisulfites, dihydroxy maleic acid, alkyl-substituted(e.g., 5-methyl reductic acid) and unsubstituted reductic acid,thioglycollate, and thiosulfate. The preferred reducing agents for useas the neutralization component of the present invention are ascorbates,particularly sodium ascorbate. The neutralization component will beutilized in an amount effective to neutralize any halogen speciesgenerated as the result of the reaction between the oxidizing andreducing agents of the disinfection component. More than thestoichiometric amount is needed to provide a reducing solution sincethese are equilibrium reactions. The amount of reducing agent requiredin order to accomplish this objective will typically be an amountsufficient to provide a concentration of about 0.001 w/v % to about 1.0w/v %. In a preferred embodiment, a 20 millimole excess of sodiumascorbate is used as the neutralization component.

The components of the present contact lens disinfection system may beformulated in various forms, in accordance with techniques known bythose skilled in the art. For example, the disinfection andneutralization components can be incorporated into a single tablet whichis composed in a manner such that the neutralization component isreleased after the lenses have been disinfected by the disinfectioncomponent. Separate tablets, solutions, or any combination thereof, canalso be utilized, so long as the neutralization component is releasedinto the system after a slight time delay, in order to allow thedisinfection component to work.

Release of the ingredients of the neutralization component into thesaline solution or other suitable diluent acts to neutralize thedisinfection component and must therefore be delayed. This isaccomplished either by physically delaying addition of theneutralization component to the diluent, or by utilizing a seal coatingand/or a delayed release coating to slow or delay dissolution of theneutralization component.

As will be appreciated by those skilled in the art, the seal and delayedrelease coatings may comprise various types of materials. For example,the seal coating may be composed of any of several polymeric materials,including cellulose ethers, vinyls, glycols, and acrylics, or thecoating could be composed of synthetic or natural gums, gelatin,shellac, salts (e.g., sodium chloride), saccharide alcohols (e.g.,mannitol or sorbitol), or other commonly used seal coating materials.The delayed release coating can be composed of any of several polymericmaterials, including cellulose ethers, vinyls, glycols, and acrylics.The delayed release coating may additionally include plasticizers suchas propylene glycol, polyethylene glycol, glycerin, mineral oil,vegetable oil, or other known plasticizers.

In a preferred embodiment of the present invention, the disinfectioncomponent comprises a combination of sodium dichloroisocyanurate as theoxidizing agent and potassium iodide as the reducing agent, and theneutralization component comprises sodium ascorbate. When these agentsare combined in an aqueous solution, the reaction scheme is as follows:

1) dichloroisocyanurate+H₂ O→cyanuric acid+HOCl

2) HOCl+KI→HOI+Cl⁻

HOI+I⁻ -→I₂

I₂ +I⁻ →I₃ ⁻

3) I₃ ⁻ +Ascorbate→Iodide+Dehydroascorbate

In a typical use of the present invention, the lens to be disinfected iscleaned with an approved daily cleaner and added to a specified volumeof saline solution or other suitable diluent (e.g., distilled water) ina suitable container. If hydrogen peroxide is utilized as the oxidizingagent, then the hydrogen peroxide solution can be utilized as thediluent. The tablet(s) of the present invention can be added to thediluent either immediately before or immediately after addition of thelens. As the tablet(s) dissolve, the oxidizing and reducing agents ofthe disinfection component are released into the solution and the lensesare disinfected. Release of the ingredients of the neutralizationcomponent into the solution acts to neutralize the products of thereaction between the oxidizing and reducing agents and must therefore bedelayed. This is accomplished either by physically delaying addition ofthe neutralization component, or by providing the neutralizationcomponent with a delayed release coating, as described above, in whichcase the neutralization and disinfection components can be added to thediluent at the same time.

The following examples are presented to illustrate further thedisinfection system of the present invention, but are not intended tolimit the scope of the invention in any respect.

EXAMPLE 1

The following formulation represents an embodiment of the inventionwherein the oxidizing agent portion of the disinfection component iscontained in one tablet and all other portions of the system, includingthe reducing agent portion of the disinfection component, are containedin a separate tablet.

    ______________________________________                                                            mg/Tablet                                                 ______________________________________                                        Part I -- Oxidizing Agent                                                     Ingredient                                                                    Sodium Dichloroisocyanurate                                                                          0.065                                                  Sodium Carbonate (anhydrous)                                                                        12.70                                                   Sodium Bicarbonate    13.435                                                  Adipic Acid           23.80                                                   Part II -- Reducing Agent/Neutralizing Core                                   A. Neutralizing Core                                                          Sodium Ascorbate       5.0 + 10% excess                                       Sodium Bicarbonate     8.5                                                    Citric Acid (anhydrous)                                                                              3.5                                                    Polyethylene Glycol 3,350 Powder                                                                     4.0                                                    Lactose               23.5                                                    B. Seal Coating                                                               Hydroxy Methyl Cellulose                                                                             1.125                                                  Ethanol (USP, Dehydrated)                                                                            0.017 ml                                               Purified Water         4.27                                                   C. Delayed Release Coating                                                    Acrylic Acid Ester     3.13                                                   (30% solids w/w)                                                              Polyethylene Glycol (8,000)                                                                          0.35                                                   Purified Water        24.07                                                   D. Outer Layer                                                                Potassium Iodide       2.0 + 10% excess                                       Sodium Chloride        0.94                                                   Hydroxypropyl Methyl Cellulose                                                                       0.157                                                  (2910, E-5 premium)                                                           Purified Water        18.74                                                   ______________________________________                                    

Preparation

In preparing the tablet containing the oxidizing agent, the sodiumdichloroisocyanurate and adipic acid were each passed through a suitablescreen (e.g., 200 micron mesh) or granulator prior to mixing with thesodium carbonate and sodium bicarbonate in a V-shell blender for onehour. The resultant granulation was compressed using a suitable toolingand tablet press to obtain slugs. The slugs were then broken and oncemore mixed in a V-shell blender for one hour. The granulation was thencompressed using a rotary tablet press fitted with suitable tooling intotablets weighing approximately 50 mg and having a hardness of 5 to 10Strong-Cobb units.

The ingredients of the neutralizing core were combined and formed intotablets in a similar manner. These tablets were then sequentially coatedwith a seal coating and a delayed release coating, followed by an outercoating of potassium iodide. Each of the three coating solutions wassimilarly prepared by mixing the ingredients until a homogenous mixturewas obtained. Each of the coating solutions was applied by rotating thetablets and spraying the coating solution onto the tablet.

All portions of tablet preparation should be done under low humidityconditions (below 20% relative humidity).

EXAMPLE 2

The following formulation represents an embodiment of this inventionwherein the oxidizing agent and reducing agent portions of thedisinfection component and the neutralization component are formulatedinto three separate tablets.

    ______________________________________                                                         mg/Tablet                                                    ______________________________________                                        Part I -- Disinfection Component                                              A. Reducing Agent                                                             Boric Acid         20.0                                                       Mannitol           35.0                                                       Potassium Iodide   20.0                                                       Sodium Bicarbonate 20.0                                                       Adipic Acid        15.0                                                       B. Oxidizing Agent                                                            Boric Acid         25.0                                                       Mannitol           40.0                                                       Sodium Bicarbonate 22.0                                                       Sodium Percarbonate                                                                              11.0                                                       Adipic Acid        12.0                                                       Part II -- Neutralization Component                                           Ingredient                                                                    Sodium Ascorbate   40.0                                                       Sodium Bicarbonate 10.5                                                       Citric Acid         4.5                                                       Polyethylene Glycol 3,350                                                                         5.0                                                       Lactose DT         43.0                                                       Sodium Borate      22.0                                                       ______________________________________                                    

Preparation

The tablets may be prepared in a manner similar to the proceduredescribed in Example 1, above. The same ingredients could also beformulated as a single tablet having three layers, wherein the core iscomposed of Part II and the outer layers are composed of the oxidizingand reducing agents of Part I.

EXAMPLE 3

The disinfecting effectiveness of the system of the present inventionwas evaluated by determining the rate and extent of kill for a sixlogarithm challenge inocula. Ten milliliters (ml) of sterile isotonicsaline solution were inoculated with a standardized suspension ofAspergillus fumigatus (ATCC 10894), Candida albicans (ATCC 10231),Pseudomonas aeruginosa (ATCC 15442), Serratia marcescens (ATCC 14041),and Staphylococcus aureus (ATCC 6538) to obtain a final concentration ofat least one million microorganisms per milliliter. The two tablets ofExample 1 were added to the saline suspension. At selected times, 1 mlwas withdrawn, serially diluted in Dey/Engley neutralizing broth, andpour plates prepared. Petri plates and dilution tubes were incubated andthe number of survivors recovered were quantitated.

The results demonstrated that the test system had both bactericidal andfungicidal activity. No survivors of bacteria or yeast were recoveredafter five minutes exposure. After ten minutes exposure, A. fumigatus,the most resistant microorganism tested, was reduced by at least sixlogarithms, depending on the actual microorganism concentration. Thefollowing Table shows the results of a typical experiment where theantimicrobial activity of the system of the present invention wascompared with that of 3% hydrogen peroxide against A. fumigatus.

                  TABLE 1                                                         ______________________________________                                        Relative Survivors of Aspergillus fumigatus                                   Exposure Time  Double Redox                                                                              3% H.sub.2 O.sub.2                                 ______________________________________                                        Initial        1.9 × 10.sup.6                                                                      1.9 × 10.sup.6                               10 min         2.0 × 10.sup.1                                                                      8.5 × 10.sup.5                               20 min         1.5 × 10.sup.1                                                                      6.0 × 10.sup.5                               ______________________________________                                    

The overall efficacy of the system of the present invention fordisinfecting contact lenses was also determined. Ten soft contact lensesbelonging to FDA Lens Group IV were contaminated with one million sporesof A. fumigatus suspended in serum and dead yeast cells. Each lens wascleaned with a daily lens cleaner and rinsed with nonpreserved saline.Lenses were placed in a basket-type contact lens case. Nonpreservedsaline was added to the lens case up to the fill line (10 ml). The twotablets described in Example 1 were placed in the lens case and the lidwith the lenses screwed onto the case. After 20 minutes, each lens wasrinsed with unpreserved saline and placed in 100 ml Dey/Engley broth.The 10 ml of neutralized solution in each lens case was decanted into100 ml Dey/Engley broth. Each lens case was filled with agar containingneutralizers and the lid with baskets replaced. After two weeksincubation, the Dey/Engley broths and lens cases were observed forsurviving A. fumigatus. No A. fumigatus was recovered from any of theten lenses, their solutions, or the lens cases.

The effectiveness of the neutralization component of this system toinhibit the growth of microorganisms that may inadvertently beintroduced into the lens case subsequent to the lens disinfectionprocess was established by means of a series of similar experiments. Inthese experiments 10 ml of unpreserved saline were placed into separatesterile test tubes. The two tablets described in Example 1 were addedand allowed to dissolve. After dissolution the solution in each testtube was challenged with bacteria and fungi such that after adding themicroorganisms, the test solution contained at least 100,000 ColonyFormation Units per ml (CFU/ml). At selected times, 1 ml was withdrawnfrom each tube, serially diluted in Dey/Engley broth, pour platesprepared and survivors determined as previously described. Results of atypical experiment of this type are given in Table 2, below.

                                      TABLE 2                                     __________________________________________________________________________    Inhibition of Microorganisms                                                  by the Neutralization Component                                                             Colony Formation Units/ml                                       Microorganism Initial                                                                             1 Day 2 Days                                                                              7 Days                                                                              14 Days                                 __________________________________________________________________________    Aspergillus niger                                                                           9.1 × 10.sup.4                                                                2.3 × 10.sup.4                                                                5.8 × 10.sup.3                                                                3.3 × 10.sup.3                                                                3.9 × 10.sup.2                    Aspergillus fumigatus                                                                       1.1 × 10.sup.5                                                                7.3 × 10.sup.4                                                                6.5 × 10.sup.4                                                                4.7 × 10.sup.4                                                                6.8 × 10.sup.3                    Candida albicans                                                                            9.0 × 10.sup.4                                                                9.8 × 10.sup.4                                                                6.0 × 10.sup.4                                                                1.4 × 10.sup.4                                                                1.0 × 10.sup.3                    Escherichia coli                                                                            1.1 × 10.sup.5                                                                7.8 × 10.sup.4                                                                6.9 × 10.sup.4                                                                1.4 × 10.sup.6                                                                5.3 × 10.sup.4                    Pseudomonas aeruginosa                                                                      8.9 × 10.sup.4                                                                2.8 × 10.sup.4                                                                1.3 × 10.sup.3                                                                <10   <10                                     Serratia marcescens                                                                         1.5 × 10.sup.5                                                                1.7 × 10.sup.5                                                                1.2 × 10.sup.5                                                                5.2 × 10.sup.3                                                                1.8 ×  10.sup.3                   Staphylococcus aureus                                                                       1.5 × 10.sup.5                                                                1.9 × 10.sup.4                                                                2.2 × 10.sup.2                                                                <10   <10                                     Staphylococcus epidermidis                                                                  6.9 × 10.sup.4                                                                1.9 × 10.sup.4                                                                1.4 × 10.sup.3                                                                <10   <10                                     __________________________________________________________________________

The neutralization component was effective in inhibiting theproliferation of bacteria, yeast and molds and maintaining theconcentration of viable microorganisms below the initial challengeconcentration.

The invention in its broader aspects is not limited to the specificdetails shown and described above. Departures may be made from suchdetails within the scope of the accompanying claims without departingfrom the principles of the invention and without sacrificing itsadvantages.

We claim:
 1. An improved method for rapidly and effectively disinfectinga contact lens, comprising:(a) providing a contact lens to bedisinfected; (b) placing the lens in an aqueous solution; (c) providinga water soluble salt of dichloroisocyanurate as a source of hypochloriteand providing a source of a water soluble iodide salt; (d) forming adisinfecting solution by releasing an antimicrobial effective amount ofhypochlorite and iodide in said aqueous solution, said hypochlorite andiodide reacting to form halogen species including iodine species,whereby the lens is rapidly and effectively disinfected by the combinedactions of the hypochlorite and the halogen species; (e) providing asource of ascorbate; and (f) releasing an amount of ascorbate in saiddisinfecting solution sufficient to neutralize said iodine species.
 2. Amethod according to claim 1, wherein the concentration of hypochloritein the disinfecting solution is 0.00001 to 1.0 w/v % and theconcentration of potassium iodide in the disinfecting solution is 0.001to 1.0 w/v %.
 3. A method according to claim 1, wherein the ascorbatepreserves the disinfecting solution against microbial contaminationfollowing disinfection of the lens.
 4. A method according to claim 1,wherein the lens is disinfected in less than ten minutes.
 5. A methodaccording to claim 1, wherein the dichloroisocyanurate salt is containedin a first tablet and is released in the aqueous solution by dissolvingsaid first tablet in the aqueous solution, and the iodide salt andascorbate are contained in a second tablet and are sequentially releasedin the aqueous solution by dissolving the second tablet in the aqueoussolution, so that the dichloroisocyanurate salt and iodide salt canreact to form iodine species and disinfect the lens prior to release ofthe ascorbate.
 6. A method according to claim 5, wherein the secondtablet includes means for delaying the release of the ascorbate relativeto the release of the iodide salt.
 7. A method according to claim 6,wherein the second tablet includes an inner core containing theascorbate, a delayed release coating surrounding the core, and an outerlayer containing the iodide salt.
 8. A method according to claim 1,wherein the water soluble salt of dichloroisocyanurate is a sodium saltand the water soluble iodide salt is a potassium salt.